The treatment of bacterial infections is a perpetual challenge in the medical community. Many powerful antibiotics exist that target different aspects of bacterial physiology. Some classes of antibiotics are toxic to bacteria, while other classes of antibiotics arrest the propagation of the bacteria in the body, giving the immune system adequate time to eliminate the bacterial infection. Penicillins, bacitracin, cephalosporins, and vancomycin disrupt the process of cell wall development in bacteria. Other antibiotics such as the aminoglycosides, chloramphenicol, erythromycin, clindamycin, tetracyclines, trimethoprim, and sulfanimides inhibit or disrupt some aspect of protein synthesis in the targeted bacteria. Still other antibiotics such as quinolones and rifampin disrupt the process of DNA or RNA synthesis in bacteria. Although the antibiotics listed above represent a powerful arsenal of treatments for bacterial infections, the increasingly widespread use of these antibiotics has resulted in the development of bacterial strains that are resistant to many of the currently available antibiotics.
Some treatment-resistant bacterial strains have plagued hospitals for decades, such as Staphylococcus aureus (responsible for Staph infections), Streptococcus pneumoniae (responsible for pneumonia and meningitis), and Proteus vulgaris (causing urinary tract infections). The incidence of infections caused by these bacteria and others show signs of increasing incidence in recent years. In 2003, epidemiologists reported that 5 to 10 percent of patients admitted to hospitals acquire an infection during their stay and that the risk for a hospital-acquired infection has risen steadily in recent decades. In November 2004, the Centers for Disease Control and Prevention (CDC) reported an increasing number of Acinetobacter baumannii bloodstream infections in patients at military medical facilities treating service members from Afghanistan and the Iraq/Kuwait region.
There exists a need to identify new and effective antibiotic compounds. Antibiotic therapies generally disrupt processes that are unique to bacteria, such as the enzymes and components of the cell wall and the prokaryote ribosomes. The efficacy and safety of antibiotics depend upon the inhibition of biochemical systems that are unique to bacteria, and that can be safely inhibited without producing detrimental or undesired side effects in the individual receiving the antibiotic therapy. As bacteria become increasingly resistant to existing therapies, it has become difficult to identify unique biochemical pathways that may be inhibited in bacteria that are not also present in the cells of the patients to be treated.
The biogenesis of cytochrome c in bacteria is a pathway that is a promising target for antibiotic therapy. Cytochrome c is an electron transport protein that is essential for most aerobic and anaerobic respiratory chains, as well as other cellular processes such as photosynthesis and apoptosis. Although three different cytochrome c biogenesis pathways have been identified in various organisms, two of these pathways are unique to bacteria and plants, and only the last remaining biogenesis pathway is unique to vertebrates, invertebrates, fungus, and some protozoa. Further, cytochrome c is synthesized on the outside of the cytoplasmic membrane of the bacteria cell, making the biogenesis of cytochrome c particularly amenable to inhibition by small molecules or proteins.
Antibiotic drug discovery is generally a random and laborious process of biological screening of compounds against a panel of known bacteria proteins. The process of antibiotic drug discovery would be greatly facilitated by a method of screening that directly measures the effects of a compound on its target protein in vivo. Further, optimizing this screening method to achieve a high-throughput screening method would greatly facilitate the process of developing new and effective antibiotics to expand the dwindling arsenal of existing antibiotics.